RBM42

RBM42 is a conserved RNA-binding protein that functions at the interface of pre-mRNA splicing and mRNA translation. In splicing, RBM42 interacts with tri-snRNP and U2AF components to promote spliceosome assembly on target transcripts, counteracting inhibitory splicing regulators such as RBM4 to facilitate processing of stress-responsive genes including CDKN1A (PMID:23437009, PMID:33976182, PMID:37993446). In translation, RBM42 associates with ribosomes and remodels 5′UTR secondary structures—notably on MYC, JUN, and EGFR mRNAs—to enable pre-initiation complex assembly, a function essential for pancreatic ductal adenocarcinoma tumorigenesis (PMID:39905246, PMID:37993446). Biallelic loss-of-function variants in RBM42 cause a multisystem neurodevelopmental disorder, and compound heterozygous mouse mutants exhibit embryonic lethality by E13.5 with widespread splicing defects (PMID:37294900).

1. 2008 High

   Establishing RBM42 as a nuclear RNA-binding protein that directly binds hnRNP K and target mRNA 3′UTRs, and relocalizes to stress granules under cellular stress, linked its function to mRNP biology and stress-responsive gene regulation.

   Evidence Reciprocal Co-IP (in vivo/in vitro), RNA binding assays on p21 3′UTR, immunofluorescence, RNAi with ATP measurement in human cells

   PMID:19170760

   Open questions at the time

   • Whether RBM42–hnRNP K interaction is RNA-dependent was not resolved
   • Mechanism by which RBM42 maintains ATP levels during stress recovery not defined
   • Genome-wide RNA target repertoire unknown
2. 2013 High

   Cross-species rescue demonstrated that RBM42's splicing function is deeply conserved, and interaction with tri-snRNP factors placed it mechanistically in spliceosome assembly.

   Evidence Human RBM42 complementation of Toxoplasma gondii TgRRM1 temperature-sensitive mutant, transcriptome-wide splicing analysis, Co-IP with tri-snRNP components

   PMID:23437009

   Open questions at the time

   • Step of spliceosome assembly at which RBM42 acts was not defined
   • RNA sequence or structural preferences for splicing targets unknown
3. 2017 Medium

   Identification of m6A as a negative regulator of RBM42–RNA binding revealed an epitranscriptomic layer controlling its target selection.

   Evidence Photo-cross-linking RNA probes ± m6A with quantitative mass spectrometry

   PMID:29140688

   Open questions at the time

   • Whether m6A-dependent loss of RBM42 binding occurs on endogenous transcripts in vivo was not tested
   • Functional consequence of m6A-mediated displacement of RBM42 unknown
4. 2019 Medium

   Linking RBM42 to MYC-driven translational programs via 5′UTR motif interactions extended its role beyond splicing to translational regulation in cancer.

   Evidence Ribosome profiling and RNA-binding protein–5′UTR motif analysis in MYC-driven lymphoma cells

   PMID:31142587

   Open questions at the time

   • Direct mechanistic role of RBM42 in translation was inferred from motif association, not from loss-of-function in this study
   • Whether RBM42 acts on 5′UTRs independently of splicing was unclear
5. 2021 High

   Defining the CAAGR RNA-binding motif and the mechanism of U2AF recruitment by RBM42 (via its fungal ortholog) provided the first sequence-level and mechanistic model for how it promotes splice-site recognition.

   Evidence CLIP-based motif identification, Co-IP with FgU2AF23, functional rescue by human RBM42, RNA-seq splicing analysis in Fusarium graminearum

   PMID:33976182

   Open questions at the time

   • Whether the CAAGR motif mediates RBM42 binding in mammalian cells was not confirmed
   • Structural basis of U2AF recruitment by RBM42 not resolved
6. 2023 High

   Genome-wide eCLIP and ribosome profiling established that RBM42 has a dual function—promoting both splicing and translation of overlapping target sets—and acts by counteracting the splicing inhibitor RBM4 at targets such as CDKN1A during the DNA damage response.

   Evidence eCLIP, RNA-seq, ribosome profiling, RNAi knockdown, interactome analysis in human cells

   PMID:37993446

   Open questions at the time

   • How RBM42 mechanistically antagonizes RBM4 at the molecular level is not defined
   • Whether splicing and translation functions are interdependent or separable was not fully resolved
7. 2024 High

   Discovery that biallelic RBM42 mutations cause a human neurodevelopmental disorder—and that a missense variant destabilizes the protein and disrupts the hnRNP K interaction—established RBM42 as essential for embryonic development and linked its molecular interactions to disease pathogenesis.

   Evidence Whole-exome sequencing of affected families, in vivo protein stability and Co-IP assays, mouse compound heterozygous model (embryonic lethality by E13.5), RNA-seq of splicing changes

   PMID:37294900

   Open questions at the time

   • Which specific splicing events drive the neurodevelopmental phenotype is not established
   • Contribution of translational versus splicing defects to the disease phenotype is unknown
8. 2025 High

   Demonstrating that RBM42 is ribosome-associated, directly remodels the MYC 5′UTR secondary structure to facilitate pre-initiation complex loading, and is required for PDAC tumorigenesis in a MYC-dependent manner unified its translational role with an oncogenic mechanism.

   Evidence CRISPRi screen, CLIP-seq, IP-MS for ribosome association, DMS-Seq RNA structure probing, xenograft models in human PDAC

   PMID:39905246

   Open questions at the time

   • Structural basis of 5′UTR remodeling by RBM42 is not resolved
   • Whether RBM42's RNA-unwinding activity requires cofactors is unknown
   • Therapeutic targeting of RBM42 in PDAC has not been explored

• Key unresolved questions include the structural basis by which RBM42 remodels RNA, whether its splicing and translational functions are mechanistically coupled or independent, and the relative contribution of each function to developmental versus oncogenic phenotypes.
• No high-resolution structure of RBM42 bound to RNA
• Separation-of-function mutations distinguishing splicing from translation roles not described
• Whether m6A regulation of RBM42 binding has physiological consequences in vivo is untested